PROJECT SUMMARY This Mentored Clinical Scientist Development Award (K08) details a five year plan to promote the independent career of Dr. Kara Maxwell as a physician scientist in translational cancer genetics. Dr. Maxwell is a PhD trained molecular and cellular biologist who is board certified in Medical Oncology. Her clinical focus is in cancer risk evaluation. Dr. Maxwell is currently an Instructor of Medicine at the University of Pennsylvania and is performing her postdoctoral research in human genetics and genomics with Dr. Katherine Nathanson. Dr. Maxwell is interested in inherited susceptibility to cancer and, specifically, how inherited mutations in DNA repair genes can direct targeted treatment of cancer. Most tumors in patients with germline mutations in the homologous recombination DNA repair genes BRCA1/2, respond to platinum agents and PARP inhibitors due to synthetic lethality. However, tumors with primary and acquired resistance to these agents exist. Dr. Maxwell's preliminary studies have shown that absence of BRCA locus-specific loss of heterozygosity (LOH) is observed in approximately 25% of primary BRCA1/2 germline mutation-associated breast and ovarian tumors. Absence of locus-specific LOH was associated with significantly lower genomic signatures of deficiency in homologous recombination DNA repair. Absence of locus-specific LOH was associated with decreased overall survival in ovarian cancer patients treated with platinum-based chemotherapy. These data suggest that BRCA1/2 locus-specific LOH could be a mechanism of primary platinum and PARP inhibitor resistance. This grant proposes to expand these preliminary studies into two clinically important categories of patients: 1) patients with inherited BRCA1/2 mutations with non-breast/ovarian tumors (Aim 1) and 2) breast cancer patients with inherited mutations in the DNA repair genes ATM and CHEK2, the two most commonly identified genes in BRCA1/2 negative breast cancer patients (Aim 2). Some tumors with primary resistance to platinum and PARP inhibitors demonstrate locus-specific LOH; therefore, other mechanisms exist. Hypomorphic, or partially functional, mutations may retain sufficient DNA repair activity to lead to primary resistance. Dr. Maxwell will test the hypothesis that hypomorphic BRCA2 mutations may demonstrate primary PARP inhibitor resistance using CRISPR-Cas9 modelling of mutations in breast cancer cell lines (Aim 3). She will supplement these studies with a career development program that takes advantage of the resources of the Basser Center for BRCA Research and broadly at UPenn. Dr. Maxwell has assembled a mentoring and advisory team of successful physician scientists and basic scientists in the biology of DNA repair to guide her career development. She will engage in didactic and hands-on training to update her molecular and cellular biological skills necessary for research in DNA repair. This career development plan and the experiments detailed in the Research Strategy will provide Dr. Maxwell the tools necessary to achieve her long-term goal of a career as a physician scientist running an independently funded laboratory studying inherited susceptibility to cancer.